Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease

被引：651

作者：

Charlton, Michael ^{[1
]}

Everson, Gregory T. ^{[2
]}

Flamm, Steven L. ^{[3
]}

Kumar, Princy ^{[4
]}

Landis, Charles ^{[5
]}

Brown, Robert S., Jr. ^{[6
]}

Fried, Michael W. ^{[7
]}

Terrault, Norah A. ^{[8
]}

O'Leary, Jacqueline G. ^{[9
]}

Vargas, Hugo E. ^{[10
]}

Kuo, Alexander ^{[11
]}

Schiff, Eugene ^{[12
]}

Sulkowski, Mark S. ^{[13
]}

Gilroy, Richard ^{[14
]}

Watt, Kymberly D. ^{[15
]}

Brown, Kimberly ^{[16
]}

Kwo, Paul ^{[17
]}

Pungpapong, Surakit ^{[18
]}

Korenblat, Kevin M. ^{[19
]}

Muir, Andrew J. ^{[20
]}

Teperman, Lewis ^{[21
]}

Fontana, Robert J. ^{[22
]}

Denning, Jill ^{[23
]}

Arterburn, Sarah ^{[23
]}

Dvory-Sobol, Hadas ^{[23
]}

Brandt-Sarif, Theo ^{[23
]}

Pang, Phillip S. ^{[23
]}

McHutchison, John G. ^{[23
]}

Reddy, K. Rajender ^{[24
]}

Afdhal, Nezam ^{[25
]}

机构：

[1] Intermt Med Ctr, Div Hepatol & Liver Transplantat, Salt Lake City, UT USA

[2] Univ Colorado Denver, Div Gastroenterol & Hepatol, Aurora, CO USA

[3] Northwestern Feinberg Sch Med, Div Gastroenterol & Hepatol, Chicago, IL USA

[4] Georgetown Univ, Div Infect Dis, Washington, DC USA

[5] Univ Washington, Harborview Med Ctr, Div Gastroenterol & Hepatol, Seattle, WA 98104 USA

[6] Columbia Univ, Med Ctr New York Presbyterian, Div Digest & Liver Dis, New York, NY USA

[7] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA

[8] Univ Calif San Francisco, Div Gastroenterol & Hepatol, San Francisco, CA 94143 USA

[9] Baylor Univ, Med Ctr, Div Gastroenterol & Hepatol, Dallas, TX USA

[10] Mayo Clin Arizona, Div Hepatol, Phoenix, AZ USA

[11] Univ Calif San Diego, Div Gastroenterol & Hepatol, San Diego, CA 92103 USA

[12] Univ Miami, Div Gastroenterol & Hepatol, Miami, FL USA

[13] Johns Hopkins Univ, Div Infect Dis, Lutherville Timonium, MD USA

[14] Univ Kansas, Med Ctr, Res Inst, Div Gastroenterol & Hepatol, Kansas City, KS 66103 USA

[15] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA

[16] Henry Ford Hlth Syst, Div Gastroenterol & Hepatol, Detroit, MI USA

[17] Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA

[18] Mayo Clin, Div Gastroenterol & Hepatol, Jacksonville, FL 32224 USA

[19] Washington Univ, Div Gastroenterol, St Louis, MO USA

[20] Duke Univ, Div Gastroenterol & Hepatol, Durham, NC USA

[21] NYU, Sch Med, Div Transplant Surg, New York, NY USA

[22] Univ Michigan, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA

[23] Gilead Sci Inc, Foster City, CA 94404 USA

[24] Univ Penn, Sch Med, Div Gastroenterol & Hepatol, Philadelphia, PA 19104 USA

[25] Beth Israel Deaconess Med Ctr, Div Gastroenterol & Hepatol, Boston, MA 02215 USA

来源：

GASTROENTEROLOGY | 2015年 / 149卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Hepatitis C Virus Infection; Decompensated Cirrhosis; Liver Transplantation; Fibrosing Cholestatic Hepatitis; FIBROSING CHOLESTATIC HEPATITIS; GENOTYPE; INFECTION; TRANSPLANTATION PATIENTS; ADEFOVIR DIPIVOXIL; C INFECTION; CIRRHOSIS; INTERFERON; RECIPIENTS; OUTCOMES; THERAPY;

D O I：

10.1053/j.gastro.2015.05.010

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1: 1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85% - 88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

引用

页码：649 / 659

页数：11

共 26 条

[1] Evolution of liver transplantation in Europe: Report of the European liver transplant registry [J].

Adam, P ;

McMaster, P ;

O'Grady, JG ;

Castaing, D ;

Klempnauer, JL ;

Jamieson, N ;

Neuhaus, P ;

Lerut, J ;

Salizzoni, M ;

Pollard, S ;

Muhlbacher, F ;

Rogiers, X ;

Valdecasas, JCG ;

Berenguer, J ;

Jaeck, D ;

Gonzalez, EM .

LIVER TRANSPLANTATION, 2003, 9 (12) :1231-1243

[2] Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection [J].

Afdhal, Nezam ;

Zeuzem, Stefan ;

Kwo, Paul ;

Chojkier, Mario ;

Gitlin, Norman ;

Puoti, Massimo ;

Romero-Gomez, Manuel ;

Zarski, Jean-Pierre ;

Agarwal, Kosh ;

Buggisch, Peter ;

Foster, Graham R. ;

Braeu, Norbert ;

Buti, Maria ;

Jacobson, Ira M. ;

Subramanian, G. Mani ;

Ding, Xiao ;

Mo, Hongmei ;

Yang, Jenny C. ;

Pang, Phillip S. ;

Symonds, William T. ;

McHutchison, John G. ;

Muir, Andrew J. ;

Mangia, Alessandra ;

Marcellin, Patrick .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (20) :1889-1898

[3] Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection [J].

Afdhal, Nezam ;

Reddy, K. Rajender ;

Nelson, David R. ;

Lawitz, Eric ;

Gordon, Stuart C. ;

Schiff, Eugene ;

Nahass, Ronald ;

Ghalib, Reem ;

Gitlin, Norman ;

Herring, Robert ;

Lalezari, Jacob ;

Younes, Ziad H. ;

Pockros, Paul J. ;

Di Bisceglie, Adrian M. ;

Arora, Sanjeev ;

Subramanian, G. Mani ;

Zhu, Yanni ;

Dvory-Sobol, Hadas ;

Yang, Jenny C. ;

Pang, Phillip S. ;

Symonds, William T. ;

McHutchison, John G. ;

Muir, Andrew J. ;

Sulkowski, Mark ;

Kwo, Paul .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (16) :1483-1493

[4]

Al Nahdi N, 2013, ANN HEPATOL, V12, P156

[5]

[Anonymous], 2014, HARV LED SOF TABL US

[6] Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation [J].

Berenguer, M ;

Prieto, M ;

Rayón, JM ;

Mora, J ;

Pastor, M ;

Ortiz, V ;

Carrasco, D ;

San Juan, F ;

Burgueño, MDJ ;

Mir, J ;

Berenguer, J .

HEPATOLOGY, 2000, 32 (04) :852-858

[7]

Berry P A, 2013, Acute Med, V12, P232

[8] Successful treatment with sofosbuvir of fibrosing cholestatic hepatitis C after liver transplantation in an HIV-HCV-coinfected patient [J].

Borentain, Patrick ;

Colson, Philippe ;

Dhiver, Catherine ;

Gregoire, Emilie ;

Hardwigsen, Jean ;

Botta-Fridlund, Danielle ;

Garcia, Stephane ;

Gerolami, Rene .

ANTIVIRAL THERAPY, 2015, 20 (03) :353-356

[9] Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS) [J].

Bourliere, Marc ;

Bronowicki, Jean-Pierre ;

de Ledinghen, Victor ;

Hezode, Christophe ;

Zoulim, Fabien ;

Mathurin, Philippe ;

Tran, Albert ;

Larrey, Dominique G. ;

Ratziu, Vlad ;

Alric, Laurent ;

Hyland, Robert H. ;

Jiang, Deyuan ;

Doehle, Brian ;

Pang, Phillip S. ;

Symonds, William T. ;

Subramanian, G. Mani ;

McHutchison, John G. ;

Marcellin, Patrick ;

Habersetzer, Francois ;

Guyader, Dominique ;

Grange, Jean-Didier ;

Loustaud-Ratti, Veronique ;

Serfaty, Lawrence ;

Metivier, Sophie ;

Leroy, Vincent ;

Abergel, Armand ;

Pol, Stanislas .

LANCET INFECTIOUS DISEASES, 2015, 15 (04) :397-404

[10] Long-term results and modeling to predict outcomes in recipients with HCV infection: Results of the NIDDK Liver Transplantation Database [J].

Charlton, M ;

Ruppert, K ;

Belle, SH ;

Bass, N ;

Schafer, D ;

Wiesner, RH ;

Detre, K ;

Wei, YL ;

Everhart, J .

LIVER TRANSPLANTATION, 2004, 10 (09) :1120-1130

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